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Update: Several hours after the initial publication of this report on September 2, Novo Nordisk announced that the FDA has extended the regulatory review for IDeglira, with a decision now expected in December. We will be presenting a separate analysis of this decision, what may have caused it, and its implications for both Novo Nordisk and Sanofi in the coming days.

The race between Novo Nordisk A/S (ADR) (NYSE:NVO) and Sanofi SA (ADR) (NYSE:SNY) combination diabetes therapies is now down to the wire, with Novo pulling ahead after a delay was slapped on Sanofi. Novo’s combination drug IDeglira puts together liraglutide with insulin degludec. Sanofi’s IGlarLixi combines its own insulin glargine with lixisenatide.

This edition of Market Exclusive’s Inside The FDA series will delve into the primary transcripts to dissect exactly why Sanofi’s combo was delayed, whereas Novo Nordisk’s was not, as well as the implications for other companies in the diabetes space considering what happened in this case, and for other biotech companies pursuing combination drugs as well. We will begin with Novo Nordisk and IDegLira.

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Most of this analysis will deal with IDegLira, and in the end we will come back to Sanofi in light of this and explain why, despite a positive panel recommendation for approval of IGlarLixi with only two no votes, the FDA still chose to delay its decision on the drug.

Novo Nordisk and IDegLira

As a brief introduction to the medications we are dealing with here, liraglutide is a subcutaneous GLP-1 drug whose activity is glucose-dependent. It generally leads to weight loss or at least weigh maintenance, and serves to activate the beta cells of the pancreas to produce insulin. Insulin degludec is a very long acting insulin analogue. IDegLira combines the two agents into a single injection.

The FDA panel discussionon this drug, which took place back in May, began with an FDA official commenting on the regulations involved in marketing combination drugs. As a reminder, FDA panelists are not bureaucrats. They are usually doctors or other professionals involved with patients in some way, invited by the FDA to vote. They do not generally have a bureaucratic mindset in terms of following regulatory guidelines robotically, if such a thing can be said.

Early on in the transcript of the discussion, before Novo Nordisk presented any data, an FDA official at the meeting noted that an improvement in glycemic control as measured by HbA1C over placebo is considered a valid surrogate of clinical benefit. HbA1C is basically a 3-month measure of blood glucose levels.

Clarifying this may seem prosaic, but that introduction is key for other diabetes-focused companies like Oramed Pharmaceuticals, Inc. (NASDAQ:ORMP), whose Phase II trial on an oral insulin pill used a placebo comparator. In other words, it is not necessary for a prospective oral insulin to go up against a subcutaneous therapy and display better results. For approval, it is enough to demonstrate efficacy over placebo.

FDA regulations regarding combination therapies like IDegLira are that the dosages have to target a significant part of the patient population for the disease, in this case diabetes. The FDA official raised the following question that the panel was instructed to consider before voting:Would it be reasonable, for example, to select an insulin-sensitive patient population who would only require low doses of the product since, at these doses, patients may be receiving a dose of 10 one of the component (sic) that is not contributing to the effect? Alternatively, in a population with severe insulin resistance, the dosage in the combination may be insufficient to provide long-term control because higher doses of insulin then can be delivered by the combination product will be required.